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We characterized two bacteriophages, ΦFG02 and ΦCO01, against clinical isolates of Acinetobacter baumannii and established that the bacterial capsule is the receptor for these phages. Phage-resistant mutants harboured loss-of-function mutations in genes responsible for capsule biosynthesis, resulting in capsule loss and disruption of phage adsorption. The phage-resistant strains were resensitized to human complement, beta-lactam antibiotics and alternative phages and exhibited diminished fitness in vivo. Using a mouse model of A. baumannii infection, we showed that phage therapy was effective. The authors characterize two phages against Acinetobacter baumannii , both in vitro and in vivo. A. baumannii strains develop resistance against both phages, but are in turn resensitized to different antimicrobial compounds.

Carbapenem-resistant Acinetobacter baumannii is responsible for frequent, hard-to-treat and often fatal healthcare-associated infections. Phage therapy, the use of viruses that infect and kill bacteria, is an approach gaining significant clinical interest to combat antibiotic-resistant infections. However, a major limitation is that bacteria can develop resistance against phages. Here, we isolated phages with activity against a panel of A. baumannii strains and focused on clinical isolates AB900 and A9844 and their phages for detailed characterization. As expected, coincubation of the phages with their hosts in vitro resulted in the emergence of phage-resistant bacterial mutants. Genome sequence analysis revealed that phage-resistant mutants harbored loss-of-function mutations in genes from the K locus, responsible for the biosynthesis of the bacterial capsule. Using molecular biology techniques, phage adsorption assays, and quantitative evaluation of capsule production, we established that the bacterial capsule serves as the primary receptor for these phages. As a collateral phenotype of impaired capsule production, the phage-resistant strains could not form biofilms, became fully sensitized to the human complement system, showed increased susceptibility to beta-lactam antibiotics, and became vulnerable to additional phages. Finally, in a murine model of bacteremia, the phage-resistant A. baumannii demonstrated a diminished capacity to colonize blood and solid tissues. This study demonstrates that phages can be used not only for their lytic activity but, if combined with a posteriori knowledge of their receptors and the mechanism of bacterial resistance, for their potential synergy with other antimicrobial agents, thus providing even broader clinical options for phage therapy.